Efficacy outcomes in trials with prophylactic hereditary angioedema therapy: A systematic review
Authors: Remy S. Petersen, Lauré M. Fijen, Danny M. Cohn
Journal: Allergy (2023)

Selecting relevant and meaningful outcomes to assess efficacy of medication is of great importance, although not devoid of challenges.1 A lack of guidance and consensus in this domain can lead to substantial heterogeneity in selected outcomes as illustrated by a recent systematic review of trials investigating acute medication for hereditary angioedema (HAE) in this Journal.2 Inconsistency in chosen outcomes hampers trial comparison, fosters the potential of selective outcome reporting bias and places a burden on trial participants when numerous outcomes are selected. With new prophylactic agents emerging, consistent outcomes are especially important in HAE research.3 Thus, in this systematic review we assessed if a similar heterogeneity in selected outcomes was present in all randomized controlled trials evaluating prophylactic treatment for HAE. The study was performed in accordance with the PRISMA-P guidelines4 and the protocol was registered in the International Prospective Register of Systematic Reviews (registration number: CRD42022374285). The search syntax for MEDLINE (Table S1) was converted to PubMed and Cochrane Central. These databases were systematically searched from their commencements until November 2022. Two researchers independently screened titles and abstracts of the resulting publications followed by full text screening. Publications reporting data from randomized controlled trials assessing prophylactic treatment in HAE patients that reported at least one outcome and were published in English were included. All outcomes reported in the methods or results section of the publication or in the protocol (when available) were extracted verbatim and converted to standardized outcome terms and classified into outcome domains by two researchers independently. Disagreements were resolved by discussion. As illustrated in Figure S1, screening of the 2951 results of the systematic search resulted in 26 eligible publications, reporting data from 22 individual trials (references in Table S2). As shown in Table 1, four standardized primary outcomes were identified. In studies published after 2002, "time-normalized attack frequency" was uniformly selected as the primary outcome, albeit the timing of measurement, and the process of adjudication varied. A larger variety of secondary and exploratory outcomes was evident, as outlined in Table 2 and Table S3, encompassing 36 standardized secondary outcomes and 34 standardized exploratory outcomes. Among studies that reported secondary and/or exploratory outcomes, all covered at least one outcome in the attack frequency domain (100%, 18/18). Additionally, a majority of these studies covered resource use (83%, 15/18), attack characteristics (78%, 14/18), and life impact (78%, 14/18) outcomes. No single outcome was employed uniformly across all trials. Table S4 lists the 16 measuring instruments that were reported in detail, of which 11 had been validated. Yet, a majority of trials utilized unspecified or non-validated instruments to collect study data. A preference for angioedema-specific tools to assess health-related quality of life was expressed in four studies (study number 3, 5, 11, and 14, references in Table S2) as these are more likely to address characteristic burdens of HAE. In this systematic review, we demonstrated that time-normalized attack frequency was consistently chosen as the primary outcome across recent studies with HAE prophylaxis. Still, we identified differences in timing and adjudication of this measurement that could be harmonized to enhance comparability of future trials. The observed heterogeneity in secondary and exploratory outcomes encompasses another area for potential improvement. In future trials, a pivotal consideration should be the selection of outcomes that are most meaningful to patients. Recent survey data revealed that patients prioritize the outcome 'number of attack-free patients'.5 Strikingly, this outcome has only been selected as a secondary or exploratory outcome in 9 of our 22 included trials. This systemic review establishes a foundation for the selection of meaningful outcomes and optimal instruments in future studies assessing efficacy of HAE prophylaxis. DC conceived of the presented research questions and supervised the project. DC and RP designed the protocol and research strategies. RP and LF screened the search results. RP and LF extracted the data from the included papers. RP performed the data analysis and took the lead in writing the manuscript. All authors discussed the results, interpreted the data and contributed to the final manuscript. The authors thank Nerissa P. Denswil for her help with the construction of the search strategies. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. RP reports speaking fees from Pharvaris. LF reports a travel grant from Ionis Pharmaceuticals inc. and consultancy fees from Pharvaris. DC reports speaking and/or consultancy fees from Astria, BioCryst, CSL Behring, Intellia, Ionis Pharmaceuticals inc., KalVista, Pharming, Pharvaris and Takeda. PROSPERO CRD42022374285. Data sharing is not applicable to this article as data for this systematic review was derived from the included publications. Figure S1. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.